Influenza Resistance to Antiviral Drugs: Virus characterization, mechanism and clinical impact

__Abstract__ Each year, approximately 5-10% of the world population is infected with the influenza viruses resulting in significant morbidity and an estimated 250.000 to 500.000 deaths every year. Among individuals at increased risk of developing severe influenza disease are those with a compromised immune system. For them being able to effectively suppress viral replication antiviral therapy can be crucial. However, in immunocompromised patients the currently available antiviral drugs show limited effectiveness. The emergence and spread of antiviral resistant viruses limit current therapeutic intervention even more. The aim of this thesis is to improve our understanding of influenza antiviral resistance. We developed new molecular tools to aid in influenza patient management, characterised a novel I222R antiviral resistance mutation and developed an immunocompromised ferret model. Finally, a key role for the influenza hemagglutinin in neuraminidase inhibitor resistance is proposed in the general discussion of this thesis. The contribution of the hemagglutinin in neuraminidase inhibitor resistance may explain the emergence of the H274Y oseltamivir-resistant influenza A/H1N1 virus in the winter season of 2007/2008

Archives in Controversy: The Press, the Documentaries and the Byrd Archives

One of the major news stories of 1996 was the discovery and analysis of Richard Byrd's diary and notebook for his North Pole flight of 1926. Byrd's claim to be the first to fly to the North Pole was challenged by his contemporaries and by later historians. The diary provided new evidence, and the news of its existence and meaning fueled stories that reached every part of the globe. Interest in Byrd also inspired producers of three documentaries. The archivist who dealt with reporters and producers discusses the media coverage, the challenges of working with reporters and producers of documentaries, and the impact of the publicity on an archival program

Extensions and block decompositions for finite-dimensional representations of equivariant map algebras

Suppose a finite group acts on a scheme $X$ and a finite-dimensional Lie algebra $\mathfrak{g}$. The associated equivariant map algebra is the Lie algebra of equivariant regular maps from $X$ to $\mathfrak{g}$. The irreducible finite-dimensional representations of these algebras were classified in previous work with P. Senesi, where it was shown that they are all tensor products of evaluation representations and one-dimensional representations. In the current paper, we describe the extensions between irreducible finite-dimensional representations of an equivariant map algebra in the case that $X$ is an affine scheme of finite type and $\mathfrak{g}$ is reductive. This allows us to also describe explicitly the blocks of the category of finite-dimensional representations in terms of spectral characters, whose definition we extend to this general setting. Applying our results to the case of generalized current algebras (the case where the group acting is trivial), we recover known results but with very different proofs. For (twisted) loop algebras, we recover known results on block decompositions (again with very different proofs) and new explicit formulas for extensions. Finally, specializing our results to the case of (twisted) multiloop algebras and generalized Onsager algebras yields previously unknown results on both extensions and block decompositions.Comment: 41 pages; v2: minor corrections, formatting changed to match published versio

Vertical migration behaviour of diatom assemblages of Wadden Sea sediments (Dangast, Germany): a study using cryo-scanning electron microscopy

The vertical migration behaviour of diatom assemblages inhabiting Wadden Sea sediments near Dangast (Germany) was investigated using cryoscanning electron microscopy. The diatom assemblages were dominated by small Navicula species. Intertidal sediments which were located at different distances from the high tide level or stayed submerged even throughout low tides were chosen. Samples were prepared and cryofixed in the field. Sampling was restricted to three sets: (i) before the onset of vertical migration, (ii) 3 to 5 h after the onset of vertical migration, and (iii) before the area became flooded again or just prior to dusk. The diatom assemblages inhabiting the different types of sediments did not always show the same response. When the tidal cycle exposed the sediment surfaces during the night cell densities increased in the early morning hours with the onset of light. Later on, although the photon flux density was still increasing, cell densities stayed constant or decreased before the water flooded the areas around noon. In experiments in which the water drained off around noon and the areas became exposed throughout the entire afternoon, cell densities increased even up to dusk when the photon flux density had dropped to values below 20 μM photons m-2s-1. In an experiment in which the last sampling occured at 10.15 pm, when the photon flux density had already declined below 10 μM photons m-2s-1, cell densities had decreased to lower values. This was ca. 1 h before the area was flooded again. Finally, cryo-scanning electron microscopy revealed frequently occuring micropatches of diatom assemblages which could be differentiated into typical areas of lower and higher cell densities further complicating the pattern of light or water cover induced movements

The Complex Langevin method: When can it be trusted?

We analyze to what extent the complex Langevin method, which is in principle capable of solving the so-called sign problems, can be considered as reliable. We give a formal derivation of the correctness and then point out various mathematical loopholes. The detailed study of some simple examples leads to practical suggestions about the application of the method.Comment: 14 pages, including several eps figures and tables; clarification and minor corrections added, to appear in PR

HoloDetect: Few-Shot Learning for Error Detection

We introduce a few-shot learning framework for error detection. We show that data augmentation (a form of weak supervision) is key to training high-quality, ML-based error detection models that require minimal human involvement. Our framework consists of two parts: (1) an expressive model to learn rich representations that capture the inherent syntactic and semantic heterogeneity of errors; and (2) a data augmentation model that, given a small seed of clean records, uses dataset-specific transformations to automatically generate additional training data. Our key insight is to learn data augmentation policies from the noisy input dataset in a weakly supervised manner. We show that our framework detects errors with an average precision of ~94% and an average recall of ~93% across a diverse array of datasets that exhibit different types and amounts of errors. We compare our approach to a comprehensive collection of error detection methods, ranging from traditional rule-based methods to ensemble-based and active learning approaches. We show that data augmentation yields an average improvement of 20 F1 points while it requires access to 3x fewer labeled examples compared to other ML approaches.Comment: 18 pages

Real-time dynamics of lattice gauge theories with a few-qubit quantum computer

Gauge theories are fundamental to our understanding of interactions between the elementary constituents of matter as mediated by gauge bosons. However, computing the real-time dynamics in gauge theories is a notorious challenge for classical computational methods. In the spirit of Feynman's vision of a quantum simulator, this has recently stimulated theoretical effort to devise schemes for simulating such theories on engineered quantum-mechanical devices, with the difficulty that gauge invariance and the associated local conservation laws (Gauss laws) need to be implemented. Here we report the first experimental demonstration of a digital quantum simulation of a lattice gauge theory, by realising 1+1-dimensional quantum electrodynamics (Schwinger model) on a few-qubit trapped-ion quantum computer. We are interested in the real-time evolution of the Schwinger mechanism, describing the instability of the bare vacuum due to quantum fluctuations, which manifests itself in the spontaneous creation of electron-positron pairs. To make efficient use of our quantum resources, we map the original problem to a spin model by eliminating the gauge fields in favour of exotic long-range interactions, which have a direct and efficient implementation on an ion trap architecture. We explore the Schwinger mechanism of particle-antiparticle generation by monitoring the mass production and the vacuum persistence amplitude. Moreover, we track the real-time evolution of entanglement in the system, which illustrates how particle creation and entanglement generation are directly related. Our work represents a first step towards quantum simulating high-energy theories with atomic physics experiments, the long-term vision being the extension to real-time quantum simulations of non-Abelian lattice gauge theories

A methodological approach to investigate steady state fucoxanthin chlorophyll a/c binding protein mRNA levels in Wadden Sea sediments

A method was established to investigate the steady state levels of mRNAs from genes encoding fucoxanthin chlorophyll a/c binding proteins (Fcp) of diatoms in situ. During the study, which was performed withWadden Sea sediments from the German North Sea shore near Dangast, oxygenic photosynthesis was carried out mainly by pennate diatoms. Field samples were taken after tidal exposure from dawn up to late afternoon at 2-hourly intervals, and frozen in liquid nitrogen. In the laboratory, total RNA was isolated by isopycnic ultracentrifugation in caesium chloride gradients. Yields of approximately 10–300 μg RNA per gram wet sediment were obtained. Defined amounts of total RNA were blotted onto nylon membranes and hybridised with probes against the fcp2 and 18S rDNA genes of Cyclotella cryptica. To estimate the steady state amount of fcp mRNAs, fcp signal intensities were normalized to the signal intensities obtained from hybridisation to an 18S rDNA gene probe. In the two time-course studies performed to demonstrate the applicability of the method, the steady state levels of fcp mRNA increased up to 12-fold with the onset of light, reaching a maximum 6–8 h after sunrise before they decreased again. Possible reasons for this time-course are discussed